Abstract
BackgroundThe issue of drug resistance in gastric cancer has attracted global attention. TSPAN9, a 4-transmembrane protein that plays an important role in tumor progression and signal transduction, has been found to be closely related to tumor invasion, metastasis, and autophagy.MethodsImmunoblotting was used to evaluate TSPAN9 expression in parental and drug-resistant gastric cancer cells. Functional assays, such as the CCK-8 assay, were used to detect the proliferation of gastric cancer cells and the response of TSPAN9 to 5-fluorouracil (5-FU). Western blotting was used to analyze the expression of constituents of the PI3K/AKT/mTOR-mediated autophagy pathway induced by TSPAN9. Coimmunoprecipitation was performed to assess the specific mechanism by which TSPAN9 affects the PI3K pathway.ResultsWe demonstrated that TSPAN9 is overexpressed in 5-FU-resistant cells compared to parental cells. 5-FU-mediated inhibition of cell proliferation can be significantly restored by increasing TSPAN9 expression, and inhibiting this expression in drug-resistant cells can restore the sensitivity of the cells to 5-FU. In addition, TSPAN9 also significantly promoted autophagy in gastric cancer cells in vitro. Further studies indicated that TSPAN9 downregulates the expression of PI3K and proteins associated with PI3K-mediated autophagy. In addition, TSPAN9 interacts with PI3K and inhibits its catalytic activity.ConclusionThe current study reveals the important role of TSPAN9 in drug resistance to 5-FU in gastric cancer. It also provides a new target to clinically address drug-resistant gastric cancer and will contribute to the treatment strategy of this disease.
Highlights
The issue of drug resistance in gastric cancer has attracted global attention
We demonstrate that TSPAN9 blocks PI3K–Akt–mTOR signaling by interacting with PI3K, which enhances autophagy and leads to 5-FU resistance in gastric cancer cells
TSPAN9 can reduce the sensitivity of gastric cancer cells to 5‐FU To investigate whether the level of TSPAN9 expression in cells is related to 5-FU resistance, we transfected AGS and MGC803 cells with TSPAN9 overexpression plasmids and treated the cells with 5-FU
Summary
The issue of drug resistance in gastric cancer has attracted global attention. TSPAN9, a 4-transmembrane protein that plays an important role in tumor progression and signal transduction, has been found to be closely related to tumor invasion, metastasis, and autophagy. Autophagy is closely related to cell differentiation and apoptosis as well as the occurrence and development of various diseases [10]. In the advanced stages of tumor development, the induction of autophagy allows cancer cells to survive under low nutrient and hypoxic conditions [11]. Chemotherapy drugs have been reported to induce autophagy by blocking the apoptotic pathway to protect tumor cells from cytotoxic death [12]. Autophagy plays an important role in the development of chemotherapy resistance during the initiation and progression of gastric cancer
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